This assignment is going to introduce the mucosal immunology and its associated components in eliciting the immune response. In the following subchapters, we identify the components of mucosal immunology in view of anatomical organization. Next, we describe the development of and maturation of the mucosal immune system as the fundamental principles to understand immune function. Then, we explain the effector mechanisms employed during encountering microbes in mucosal area with their interlink with remote body area through circulation. Finally, some disorder associated with mucosal immunology.
Introduction
REFERENCES
http://www.socmucimm.org/index.php?option=com_content&task=view&id=46&Itemid=71
http://www.nature.com/mi/journal/v1/n1/full/mi20079a.html
http://emedicine.medscape.com/article/207891-overview
http://priory.com/cmol/malt.pdf
http://www.nature.com/icb/journal/v77/n4/full/icb199947a.html
MUCOSAL FEATURES ANATOMICAL
In mucosal immunization, the term mucosal-associated lymphoid tissues (MALT) was first coined to emphasize that solitary organized mucosa-associated B-cell follicles and larger lymphoid aggregates have common features and are the origin of cells that traffic to mucosal effector sites. The components of MALT are sometimes subdivided into (1) GALT (gut-associated lymphoid tissue.), (2) BALT (bronchus-associated lymphoid tissue), (3) NALT (nose-associated lymphoid tissue), (4) LALT (larynx-associated lymphoid tissue), (5)SALT (skin-associated lymphoid tissue), (6) VALT (vascular-associated lymphoid tissue.), and (7)EALT (eye-associated lymphoid tissue). MALT is sub-divided according to anatomical regions. Also the age and tissue state (normal or chronically inflamed) have an impact on the appearance of MALT. In contrast to peyer's patch and tonsils, other human MALT structures do not apparently develop prenatally, and their occurrence and size generally depend on induction by exogenous stimuli. For instance, bronchus-associated lymphoid tissue (BALT) is not regularly found in normal lungs of adults. Notably, all MALT structures resemble lymph nodes with variable T-cell zones intervening between the B-cell follicles and contain a variety of antigen-presenting cells, including dendritic cells and macrophages. However, MALT lacks afferent lymphatics because all such lymphoid structures actively sample exogenous antigens directly from the mucosal surfaces through a characteristic follicle-associated epithelium containing "microfold" or "membrane" (M) cells. These specialized thin epithelial cells effectively transfer soluble and especially particulate antigens such as microorganisms from the gut lumen. Gut-associated lymphoid tissue (GALT) comprises peyer's patch, the appendix, and isolated lymphoid follicles (ILFs), which are considered inductive sites for mucosal B and T cells. The occurrence of other GALT-like elements such as lymphocyte-filled villi and cryptopatches is species-dependent, and these structures do not appear to be involved in B-cell induction. These small lymphoid structures may instead, represent precursons of marine ILFs.
A detailed understanding of the anatomical sites and physiology of mammalian MALT is a necessary preamble prior to focusing on the interaction of mycobacteria and lymphoepithelial tissues. Mucosal lymphoid tissues are anatomically widespread but common to most mammals. Their individual constituents include: (i) a ring of lymphoid structures circling the pharynx (Waldeyer's ring), principally the oropharyngeal and nasopharyngeal tonsils but also including tubal and lingual tonsils in some species; (ii) larynx-associated lymphoid tissue (LALT); (iii) intestinal Peyer's patches; (iv) appendix; (v) aggregated lymphoid nodules in the large intestine; (vi) isolated lymphoid nodules throughout the gut from the oesophagus to the anus; (vii) the bronchus-associated lymphoid tissue (BALT); and (viii) conjunctiva-associated lymphoid tissue (CALT). These tissues are concentrated at sites of greatest microbial concentration and antigenic challenge. Mucosa-associated lymphoid tissues are composed of a specialized follicle-associated epithelium (FAE) that actively take up macromolecules and micro-organisms. Associated with the FAE and lying in the lamina propria are the secondary lymphoid follicles containing germinal centres. Despite species and site differences in gross anatomical detail, especially in the oropharyngeal tonsils, the fine structure and gross functional characteristics appear to be similar across species. The basic function of the FAE is to provide a favourable environment for the contact between antigens, intra-epithelial lymphocytes and antigen-presenting cells (APC). Once antigenic contact has been made, MALT has a complex dual role to fulfil. First, it must maintain a capacity to recognize pathogens and mount an appropriate protective immune response. This immune exclusion principally involves secretory antibodies, particularly IgA. The second function is that of suppression of local and peripheral hypersensitivity to innocuous substances on the mucosal surface. This prevents inappropriate tissue-damaging or energy-wasting responses.
The lumenal surface of lymphoepithelial tissues contains patches of epithelium covered by a protective glycocalyx and mucous layer, interspersed with areas of reticulated epithelium. This reticulated area is composed of scattered M cells, lymphoid cells and the normal epithelial cell types of the surrounding mucosa. The M cells function as selective, but active, macromolecule uptake and transport cells. The absence of an overlying layer of mucous or glycocalyx and the paucity of microvilli allow pathogens access to the folded M cell surface and promote adherence. Vesicles, arising from cytoplasmic projections that surround and engulf lumenal material, are abundant in the apical cytoplasm. These vesicles are the means by which micro-organisms and macromolecules are endocytosed, rapidly transported through the M cell and discharged into the supranuclear intercellular spaces within hours of engulfment. Macromolecule transport probably occurs with little or no enzymatic destruction, loss of antigenicity or microbial viability. Dendritic cells, macrophages, T and B lymphocytes, plasma cells and occasional polymorphonuclear leucocytes infiltrate the epithelium in these areas. These accessory cells migrate through the fenestrated basement membrane of the FAE and move through intra-epithelial passageways that form in response to the flexible nature of the M cells and their attachments. In this way, the M cells facilitate the ingress of lymphoid cells into the lumen of the viscus. The ability of the cytoskeleton to rearrange itself and redistribute desmosomal contacts indicates that this epithelium is dynamic and responsive, presumably to antigenic stimulation. Such antigenic bombardment will stimulate a greater influx of non-epithelial cells and cause a thinning of the epithelium. In the extreme, inflammatory reactions will result in more lymphoid cells being expelled from the surface of the epithelium. This may lead to complete loss of epithelial integrity, with direct exposure of lymphoid cells to the lumen of the viscus.
Schematic representation of a section of Peyer's patch lymphoepithelium. Mycobacteria that are free in the intestinal lumen adhere to microfolds and are endodocytosed by the M cells (M), that present bacilli to underlying dendritic cells (D) and macrophages (Mac). These, and accompanying lymphocytes (L), lie in the dome area above the lymphoid follicles. Macrophage and dendritic cell traffic may carry the bacilli to other sites in the body or back through the lymphoepithelium to the mucosal surface. Normal epithelial cells (E) appear to take no part in the processing of particulate antigens.
This figures is the illustration of three mucosal immune-cell compartments.
Figure (a,b)illustrate the three-color immunofluorescence staining of B cells (CD20, green), T cells (CD3, red), and epithelium (cytokeratin, blue) in cryosection of human Peyer's patch.
Figure (b)is the details from the M-cell areas framed on the left in the follicle-associated epitheliumin the figure (a) covering a B-cell follicle.
Figure (c)is the two-color immunofluorescence staining for IgA (green) and IgG (red) in a section from normal human large bowel mucosa. Crypt epithelium shows selective transport of IgA, and only a few scattered IgG-producing cells are seen in the lamina propria together with numerous IgA plasma cells.
Figure (d) is the three-color immunofluorescence staining for CD4+ (red) and CD8+ (green) T cells in normal human duodenal mucosa. The epithelium of the villi is blue (cytokeratin). Note that most of the elements with weak CD4 expression seen in the background are either macrophages or dendritic cells.
http://onlinelibrary.wiley.com/doi/10.1016/j.femsim.2004.06.012/abstract
http://www.vetres-archive.org/file/Vet.Res._0928-4249_2006_37_3/Vet.Res._0928-4249_2006_37_3_ART0012.pdf
http://journals.cambridge.org/download.php?file=%2FPNS%2FPNS64_04%2FS0029665105000546a.pdf&code
Vega-Lopez MA, Telemo E, Bailey M, Stevens K & Stokes CR(1993) Immune cell distribution in the small-intestine of the pig - immunohistological evidence for an organized compartmentalization in the lamina propria. Veterinary Immunology and Immunopathology 37, 49-60.
Adkins B, Jones M, Bu YR & Levy RB (2004) Neonatal tolerance revisited again: speciï¬c CTL priming in mouse neonates exposed to small numbers of semi- or fully allogeneic spleen cells. European Journal of Immunology 34, 1901-1909.
Peng HJ, Turner MW & Strobel S (1989) Failure to induce oral tolerance to protein antigens in neonatal mice can be corrected by transfer of adult spleen-cells. Pediatric Research 26,486-490.
Development and Maturation of Mucosal Immunity
There is considerable evidence to indicate that the immune system of neonates is relatively undeveloped compared with that of adults, particularly the mucosal immune system (Vega-Lopez et al. 1995). Consistent with this observation, newborn animals mount poor responses to antigen, and can often be tolerised by doses of antigen that trigger active responses in adults (Adkins et al. 2004). Further, they are difï¬cult to tolerise orally (Peng et al. 1989), indicating that the major functions of the systemic and mucosal immune systems are defective at birth. Together, these factors probably help to prevent inappropriate immune responses to the range of novel antigens presented to the newborn animal. The structures of the mucosal immune system are fully developed in uterus by 28 weeks gestation, but in the absence of intrauterine infection, activation does not occur until after birth. Mucosal immune responses occur rapidly in the first weeks of life in response to extensive antigenic exposure. Maturation of the mucosal immune system and establishment of protective immunity varies between individuals but is usually fully developed in the first year of life, irrespective of gestational age at birth. In addition to exposure to pathogenic and commensal bacteria, the major modifier of the developmental patterns in the neonatal period is infant feeding practices. A period of heightened immune responses occurs during the maturation process, particularly between 1 and 6 months, which coincides with the age range during which most cases of sudden infant death syndrome (SIDS) occur. A hyper-immune mucosal response has been a common finding in infants whose death is classified as SIDS, particularly if in association with a prior upper respiratory infection. Inappropriate mucosal immune responses to an otherwise innocuous common antigen and the resulting inflammatory processes have been proposed as factors contributing to SIDS.
Development of the diffuse lymphoid architecture in the neonate
Table I. Stages in the development of the mucosal immune system of the neonatal piglet.
Stage 1
The newborn pig
Small numbers of antigen-presenting cells
Essentially no plasma cells
Few T-cells
Stage 2
1 day to 2
Appearance of unusual CD2+CD4-CD8- and CD2+CD4-CD8αα T-cells weeks in epithelium and lamina propria Appearance of some activated CD4+ T-cells in lamina propria Influx of MHCII+ cells in lamina propria
Stage 3
2 weeks to 4 weeks
Mature memory CD4+ T-cells in lamina propria
IgM+ B cells, predominantly in crypt areas
Stage 4
4 weeks to 6 weeks
Appearance of memory CD8+ T-cells in epithelium and lamina propria
IgA+ B cells, predominantly in crypt areas
Despite the size of the immunological component of the mucosa in adults, only small numbers of leucocytes are present in this tissue at birth or hatching. In particular, newborn piglets have essentially no leucocytes, despite the more advanced development of piglets at term compared to human or rodent neonates]. This is true for lamina propria leucocytes of any type,including antigen presenting cells, T-cells or B cells .The relatively impermeable epitheliochorial placenta of the pig, which does not permit the transfer of macromolecules from sow to foetus, either antibody or exogenous antigen, makes the newborn piglet entirely immunologically naïve and may explain this profound lack of immune development of the newborn piglet. This fact has made the pig the model of choice for studies of the impact of environmental factors on immune development. It has been shown that these leucocyte populations appear in conventional pigs in a clearly staged time course, where different phases can be distinguished (Tab. I). Strongly MHC II+ cells, characterised as dendritic cells by co-expression of CD45, CD16 and other myeloid markers appear relatively quickly and in large numbers in this site, within the first week of age. Initially, a subset expresses CD14, but in older animals, MHC II+CD45+CD16+ cells lack CD14. This suggests that some of these dendritic cells may be derived from blood monocytes, and may explain the fact that there appears to be some controversy about the classification of antigen-presenting cells in the gut as dendritic cells or macrophages. In contrast, T-cells appear more slowly. The T-cell population itself can be shown to undergo a phased pattern of appearance .An unusual cell type, characterised by the expression of CD2, but lacking CD4 and CD8, has recently been shown to co-express CD3 and can therefore be classified as CD4-CD8- T-cells. Together with a second T-cell population, characterised as CD2+CD3+CD4-CD8αα+, they form the dominant T-cells migrating into the jejuna tissue during the first week to ten days, and can still be found in adult animals, albeit in reduced proportions. These cells appear to have characteristics similar to the subset of thymus-derived cells with re-arranged TCR, but lacking co-receptors, which have been shown to leave the chicken thymus early and acquire CD8αα expression in the gut. Similarly, CD4-negative CD8αα intraepithelial T lymphocytes have been described in rodents and have been included in the broad classification of "unconventional" or "type B" T-cells, suggested to be involved in a number of functions including immune regulation. Interestingly, while conventional CD4+ and CD8αβ+ T-cells in this site in adult animals express low levels of CD45RC, consistent with advanced memory status, a significant proportion of these unusual, CD2+CD3+CD4-CD8αα+ T-cells express moderate to high levels of CD45RC, suggesting that they may be less antigen-experienced. High CD25 expression during the early time points, i.e. the first week to ten days of life, also suggests that they arrive with or acquire an activated status in the gut of very young animals .During the second and third week of life, increasing numbers of CD4+ T-cells appear. Like the CD4-CD8αα+ T-cells, CD4+ T-cells appear in the very young animals with signs of recent activation: that is, expressing high levels of CD25 and also CD8αα (the expression of CD8αα on pig CD4+ cells has been described in other tissues and has been associated with memory status,) and moderate levels of CD45RC, suggesting that these are cells with recent antigenic activation, in transit towards a memory status. This contrasts with the cellular characteristics of CD4+ T-cells in animals older than 12 days, which by phenotype are resting cells but of advanced memory status (lack of CD45RC, lower levels of CD8αα and CD25, high levels of SwC1) and respond to polyclonal activation by expression of IL-4 mRNA but not IL-2. Finally, considerable numbers of true cytotoxic T-cells, characterised by high levels of CD8, appear. Significant numbers are only observed after the third week of life, although, again, a small proportion of such cells can be found as early as the first week. Like the other T-cells, the CD8 cells arriving in the youngest pigs show signs of cellular activation and are in the early stages of a memory phenotype, whereas CD8 in older animals are resting, advanced memory cells. Other late arrivals in the gut are IgA+ plasma cells, which have been reported to appear in significant numbers as late as 3-6 weeks. Summarising, the final architecture characteristic of the diffuse lymphoid tissue of the gut is not achieved until the pig is approximately six weeks old, containing large numbers of dendritic cells, CD4+ T-cells of resting, advanced memory phenotype, transcribing IL-4 but unable to secrete IL-2 and responding to further activation by apoptosis.
DEFENSE MECHANISM OF MUCOSAL IMMUNITY
Epithelial surfaces are immediately after birth coming into contact with numbers of micro-organisms. These surfaces therefore evolved a number of protective mechanisms to resist the invasion of micro-organisms. While the skin surface is protected mechanically by several epithelial layers, surfaces of the gastrointestinal, respiratory and urogenital tracts, conjunctivae and outlets of endocrine glands are mostly covered with a single-layered epithelium and require, therefore, a more extensive protection: this is represented by a complex of mechanical and chemical agents responsible for effective degradation and removal of heterogeneous substances. In addition, both mucosa and internal environment of the organism are protected by a most effective innate and highly specific immune systems. Basic functions of the mucosal immune system are protection against pathogenic micro-organisms and prevention of penetration of immunogenic components from mucosal surfaces into the internal environment of the organism (barrier and anti-infectious functions). Another important function is induction of unresponsiveness of the systemic immunity to antigens present on mucosal surfaces.
Innate Defence Mechanism
A basic mechanism of mucosal immunity is innate, natural immunity represented by processes that protect the host immediately, within the first minutes and hours, of exposure to infection. It is of interest that these defense mechanisms of vertebrates are implemented by structurally related effector molecules present in plants and insects, which do not possesses higher, specialised forms of adaptive immunity. A characteristic, although not yet clearly defined, feature of innate immunity is an ability of distinguishing between potentially pathogenic microbial components and harmless antigens by "pattern recognition receptors (PRRs)". An example of these molecules is the so-called Toll-like receptors (TLRs) enabling mammalian cells to recognise conserved characteristic molecules present on micro-organisms and described as pathogen-associated molecular patterns (PAMP). As these molecules e.g. lipopolysaccharides, peptidoglycans and others are present also on commensal bacteria it seems more precise to call them microbe-associated molecular pattern (MAMP). Toll receptors were originally described in Drosophila as transmembrane receptors, their extracellular domain contain leucine-rich repeat whereas cytoplasmic domain is homologous to IL-1R, in insects they were found to play an essential role in the immune response to fungal infection. In mammals, PRRs are present on macrophages, neutrophils, dendritic cells and other cells belonging to innate immune system. It was demonstrated that recognition of microbes activates NfκB signalling pathway and in this way it triggers cytokine production, up-regulation of co-stimulatory molecules on antigen presenting cells leading to activation of T cells. Innate defence mechanism consists of barrier function, proteolytic enzyme, antimicrobial molecules, and commensal organism.
Barrier function consists of glycocalyx and epithelial cell tight junction. Glycocalyx contain goblet cells that produce mucous to create a thick barrier that covers the GI epithelium and prevents easy access. Hence, pathogens become trapped in the mucous and are expelled via peristalsis. Mucous also acts as a reservoir for secretory IgA. On the other hand, epithelial cell tight junction prevents the passages of macromolecules. This junction contain zonulin that being upregulated during the acute phase of celiac disease. Besides, it induces tight junction disassembly and increased intestinal permeability.
Figure 1: Glycocalyx structure Figure 2: Tight junction structure
Proteolytic enzyme is an enzymes in the stomach (pepsin) and small bowel (trypsin, chymotrypsin, pancreatic proteases) that break down large polypeptides into di-peptides and tri-peptides. Peptides less than 8-10 amino acid are poor immunogens. These enzymes are very cytotoxic to pathogens.
Antimicrobial molecule contains several enzymes that play a role in defence mechanism. Lactoferrin are enzyme that binds iron and inhibits bacterial growth. Besides, Lysozyme cleaves cell wall of gram positive bacteria. Defensins, a 30-40 amino acid peptides that disrupts the cell membranes of bacteria and fungi causing lysis.
Commensal organisms consist of more than 400 species of commensal bacteria that provide enzymatic breakdown of food. This organism competes with pathogenic bacteria for space and nutrients and prevents colonization of the gut. It also has antibiotics that disrupt homeostasis
Adaptive response
The initiation or inducting areas have similar elements to those of the systemic immune system for trapping antigens and beginning the immune response. With the sole exception of the M cells, which are epithelial cells specialized in antigen transportation, the rest of the cellular components (antigen presenting cells, T and B lymphocytes) act in a similar way to the systemic immune system. They are located in the tonsils, Peyer´s platelets and diffuse lymphoid tissue. In summary, antigen binding, transportation, processing and T and B presentation take place in GALT and BALT areas.
Antigens usually enter the organism through inhalation or ingestion. By means of a process mediated by M cells, APCs or B lymphocytes (similar to the cell cooperation), there will be a B (mainly IgA producers) and T lymphocyte stimulation. The stimulated cells will leave the initiating areas through the circulation and will migrate to different effectors areas. This mechanism enables a generalized response even though the antigenic stimulation has been in a local level. This immune response is known as the generalized secreting response.
Figure 3: Stimulation of mucosal-associated lymphoid tissue, BALT or GALT. This mechanism allows a generalized response even when the antigenic stimulation has been a local process.
Most of the immune cells present in the effector areas are T lymphocytes which are located among epithelial cells or beneath them, in the lamina propria. Some B lymphocytes are also present and they can react with the antigen. Plasma cells, secreting mainly IgA immunoglobulin, are situated in lymph nodes and in diffuse lymphatic tissue of gastrointestinal and respiratory walls. These cells play a major role in the mucosa immune response, secreting about 80% of the IgA produced, with the exception of the tonsils, where IgG is the predominant immunoglobulin, followed by IgA. IgA play a role in inhibits microbial adherence, neutralizes viruses and toxins, and neutralizes catalytic activity of microbial enzyme.Its dimeric or tetrameric structure allows 4 to 8 immunoglobulin binding sites. This makes it tremendously effective against different bacterial antigens by means of ADCC reactions; IgA is not a bactericide. It does however, have the capability of neutralizing several viruses, even inside epithelial cells. In fact, it is the only immunoglobulin able to work in the cell interior. Nevertheless, the main activity of the IgA in the mucosal defense is to avoid the attachment of bacteria and viruses to the epithelium surface. Thus, the IgA can have its activity in three different ways: firstly, it can bind the antigen in the gastrointestinal lumen, preventing antigen attachment to the epithelial surface; second, it can act inside enterocytes, and finally, in the extracellular fluid.
Antigen transportation to the inductor areas (Peyer´s platelets and lymphoid follicles) is mainly done by what are called M-cells. M-cells are epithelium cells specialized in antigen transportation. They do not act enzymatically against antigens. M-cells trap antigens in the gastrointestinal lumen and carry them to epithelial lymphocytes or enter through the inter-cellular gap to the extracellular fluid, where they present the antigen to APC (macrophages, dendritic cells and B lymphocytes) of the sub-epithelial area or lamina propria. The activation mechanisms in the lamina propria follow a similar pattern to the one for the cellular cooperation described above.
Figure 4: ANTIGEN PRESENTATION IN THE INDUCTING AREA OF THE MUCOSA. Antigens that enter the enterocytes are readily destroyed by the activity of the lysosomes. However, those antigens bound by M-cells are transported without being degraded and eventually presented to epithelial lymphocytes. Then, they are transported to the lymphatic nodes.
Antigen presentation can also occur in the effectors areas, although the entry mechanism is usually different to that of the inducting areas. Antigens can enter the effectors area by endocytosis or through gap junctions. Antigen binding and presentation are performed by macrophages, M-cells or B lymphocytes, and the subsequent stages follow the same mechanisms described above.
The immune response induced in the mucosa usually needs a larger quantity of antigen, and sometimes also a greater number of immunizations, than that of the systemic system. This is especially true in the case of oral immunizations. This is due to the antigens suffering a series of enzymatic alterations and degradations when they enter the organism by this mechanism. This mechanism is good for the animal immune defense but must be taken into account when preparing oral vaccines. There are however, several strategies used to produce a good oral immune response. Nevertheless, the induction of immunity in the respiratory tract is generally easier by an oral immunization than by producing immunity in the gastrointestinal mucosa by a nasal immunization.
Figure 5: Antigen in the effector area, where it enters by endocytosis mechanisms or through the gap junctions.
Figure 6. M cells and the induction of mucosal immunity. M cells are present in mucosal inductive sites in both the intestinal and upper respiratory tract, specifically in Peyers patches and the nasal-associated lymphoid tissue, the tonsils and adenoids. M cells are thought to play an important role in antigen processing and possibly the induction of antigen-specific mucosal immunity in mucosal effector sites. Sites followed by question marks are presumed sites since limited data are available on these sites.
Figure 7: Antigen uptake and recognition by CD4+ T cells in the intestine
Antigen might enter through the microfold (M) cells in the follicle-associated epithelium (FAE) (a), and after transfer to local dendritic cells (DCs), might then be presented directly to T cells in the Peyer's patch (b). Alternatively, antigen or antigen-loaded DCs from the Peyer's patch might gain access to draining lymph (c), with subsequent T-cell recognition in the mesenteric lymph nodes (MLNs) (d). A similar process of antigen or antigen-presenting cell (APC) dissemination to MLNs might occur if antigen enters through the epithelium covering the villus lamina propria (e), but in this case, there is the further possibility that MHC class II+ enterocytes might act as local APCs (f). In all cases, the antigen-responsive CD4+ T cells acquire expression of the integrin and the chemokine receptor CCR9, leave the MLN in the efferent lymph (g) and after entering the bloodstream through the thoracic duct, exit into the mucosa through vessels in the lamina propria. T cells which have recognized antigen first in the MLN might also disseminate from the bloodstream throughout the peripheral immune system. Antigen might also gain direct access to the bloodstream from the gut (h) and interact with T cells in peripheral lymphoid tissues
IgA Defiency
Approximately one out of every 600 people have selective IgA deficiency. Among those, people of European ancestry greatly out number those are of other ethnic groups. Selective IgA Deficiency is relatively common in Caucasians.People with this deficiency lack immunoglobulin A (IgA), a type of antibody that protects against infections of the mucous membranes lining the mouth, airways, and digestive tract. Most affected people have no illness and are asymptomatic as a result.
What causes IgA deficiency?
IgA deficiency is caused by faulty white blood cells called B cells or B lymphocytes. While patients have normal numbers of B cells, these cells do not mature into normal IgA-producing cells. Scientists do not know the exact cause or causes for these immature B cells. Sometimes clusters of cases occur in families. But, almost all IgA deficient patient posses circulating B cell bearing surface IgA but these appear immature,as stated previously. Often are coexpress IgM and it fail to differentiate into IgA-secreting plasma. In some cases plasma cell,produce IgA2 subclasses are present in gut with the defect confined with IgA1 producing bone marrow plasma cell. Circulating T cell which block the differentiation of IgA plasma cell also have been identified in some patient with IgA defiency.
Some Clinical features of IgA deficiency
HIV-1 infection and autoimmune diseases
One of major problem in IgA deficiency is the occurrence of autoimmune diseases. These are found in about 25% to 33% of patients who seek medical help. In autoimmune diseases, individuals produce antibodies or T-lymphocytes which react with their own tissues with resulting inflammation and damage. Some of the more frequent autoimmune diseases associated with IgA deficiency are Rheumatoid Arthritis, Systemic Lupus Erythematosis and Immune Thrombocytopenic Purpura (ITP).These autoimmune diseases may cause sore and swollen joints of the hands or knees, a rash on the face, anemia (a low red blood cell count) or thrombocytopenia (a low platelet count). Other kinds of autoimmune disease may also affect the endocrine system and the gastrointestinal system. For HIV, mucosal tissue of genital and intestinal tracts are the most important portal of entry of HIV. Epidemiocological studies prove that 80%-90% of HIV infection are acquired by mucosal route through heterosexual and homosexual intercourse and vertical tramsmision routes in utero.Previous study indicate that SIV (simmian immunodefiency viruses) and HIV primarily targets and destroy mucosal CD4+ cells perhaps due to selective expression of chemokine receptor. In addition to the initial HIV infection sites, mucosal tisues especially gastrointestinal sites are involved in chronic activation of systemic immune system,a hallmark of progressive HIV infection. Some study also shown that microbial translocation from GIT mucosa to systemic compartment with chronic activation via innate and acquired immune system, provide evidence for these.
Mucosal allergies
Hypersecretion of mucus can occur in inflammatory respiratory diseases such as respiratory allergies, asthma, and chronic bronchitis. Allergies may also be more common among individuals with Selective IgA Deficiency than among the general population. These occur in about 10-15% of these patients. The types of allergies are vary. Asthma is one of the common severe atopic allergic diseases that occurs with Selective IgA Deficiency, which also include allergic rhenitis. In asthmatics, 20-25% of airway epithelial cells are goblet cells, even in mild disease . All of these diseases have distinct etiologies and different inflammatory responses that drive mucous hypersecretion. In asthma, inflammation appears to be mediated by allergen-specific Th2 cells, leading to eosinophilia. It has been suggested that asthma may be more severe, and less responsive to therapy, in individuals with IgA deficiency than it is in normal individuals. Mucous secretions in the airways in asthma appear to be a major cause of airway obstruction, ventilation-perfusion mismatching, and hypoxemia, leading to wheezing and dyspnea .Another type of allergy associated with IgA deficiency is food allergy, in which patients have reactions to certain foods. Symptoms associated with food allergies are diarrhea or abdominal cramping. It is not certain whether there is an increased incidence of allergic rhinitis (hay fever) or eczema in Selective IgA Deficiency.
Cystic fibrosis and pneumonia
Pneumonia is an infection of the lungs. It involves the tiny air sacs, called alveoli, which are located at the tips of the body's smallest breathing tubes, called the bronchi. The alveoli are responsible for passing oxygen into the blood. Pneumonia is an inflammation of the lung caused by infection with bacteria, viruses, or other organisms. Pneumonia is usually triggered when a person's defense system is weakened, most often by a simple viral upper respiratory tract infection or a case of influenza (the flu). Such infections or other triggers do not cause pneumonia directly but they alter the protective blanket of mucous in the lungs,make the mucous become thickening and thus encouraging bacterial growth. For cystic fibrosis, it is caused by a defective gene which causes the body to produce abnormally thick and sticky fluid, called mucus. This mucus builds up in the breathing passages of the lungs and in the pancreas, the organ that helps to break down and absorb food.This collection of sticky mucus results in life-threatening lung infections and serious digestion problems. The disease may also affect the sweat glands and a man's reproductive system. Millions of Americans carry the defective CF gene, but do not have any symptoms. That's because a person with CF must inherit two defective CF genes which one are from each parent.
This is the differences between the normal lung structures of mucus of a normal person with the thick mucus in lung of the cystic fibrosis or pneumonia patient.
